[1614-12-6]  · C6H6N4  · 1-Aminobenzotriazole  · (MW 134.06)

(an important precursor of benzyne, by oxidation with lead tetraacetate;1 this method of benzyne generation is especially useful for biphenylene formation and other [2 + 2],1c [3 + 2],19 and [4 + 2]22 cycloadditions)

Alternate Name: 1H-benzotriazol-1-amine.

Physical Data: colorless to tan solid, mp 83-84 °C;1c 1H NMR;1c 15N NMR.2

Solubility: sol benzene, CH2Cl2, CHCl3.

Form Supplied in: commercially available.

Preparative Methods: by amination of benzotriazole with Hydroxylamine-O-sulfonic Acid, or from o-nitroaniline by a multistep route.1c

Handling, Storage, and Precautions: toxicity and carcinogenicity not known; reacts rapidly with various oxidizing agents to generate benzyne.

Formation of Benzyne.

Campbell and Rees discovered that benzyne is efficiently generated by the Lead(IV) Acetate (LTA) oxidation of the title compound (1), as shown by high yield [4 + 2] trapping with Tetraphenylcyclopentadienone (2) (eq 1).1 Benzyne is not only formed and trapped efficiently when (1) is added to LTA, but also when the order of addition is reversed; the latter is somewhat surprising, since excess (1) can function as a nucleophile to destroy benzyne, as observed when oxidation of (1) is effected with (Diacetoxyiodo)benzene.3 A recent modification4 of the Campbell-Rees method, simultaneous addition of LTA and (1) to opposite ports of a stirred flask, has led to improvement in some applications, e.g. [4 + 2] reactions with oxazoles,4 vinyl isocyanates,5 and 1,2,4-triazines.6

The major advantages of the (1) + LTA method, compared with other procedures for generating benzyne, are: (a) the reaction is rapid over a wide temperature range, from at least -70 to +55 °C;1c (b) the reagents are compatible with base-sensitive materials and most functional groups; and (c) although all of the aminobenzotriazole substrates must be prepared, the method has considerable demonstrated generality (see below). Disadvantages (side reactions) stem from the powerful oxidizing ability of LTA, and the formation of HOAc in the reaction.

Preparative Methods.

Campbell and Rees also developed two preparative routes to (1).1c These remain the methods of choice for (1), as well as for analogs. The simpler procedure involves amination of benzotriazole with NH2OSO3H, which gives a mixture of (1) and 2-aminobenzotriazole (3) (eq 2).1c Compounds (1) and (3) can be separated by chromatography, although this may not be important in many applications. The reaction of (3) with LTA affords cis,cis-muconodinitrile, which reportedly does not interfere with the benzyne formed from (1).1c

The second preparative method for (1) is based on an earlier literature report, improved by Campbell and Rees.1 Diazotization of o-nitroaniline followed by treatment with diethyl malonate gives the derivative (4); reduction of the nitro group and cyclization via diazotization affords (5), which is then hydrolyzed to (1) (eq 3).

Analogs of (1).

The known substituted derivatives, benzologs, and heteroaromatic analogs of (1) that have been used to generate arynes are displayed as structures (6)-(22),1c,5,7-14 along with the related nonoxidative precursor of benzyne (23),15 and the aminotriazene precursor of cycloheptyne (24).16

[2 + 2] Reactions.

One of the most striking and unusual features of the LTA oxidation of (1) is the high yield of o-biphenylene (25) that is formed when the reaction is carried out in the absence of an efficient aryne-trapping agent (eq 4).1c The high yield of (25) requires that the benzyne concentration exceed [10-7], even if the [2 + 2] reaction occurs at the diffusion-controlled limit. In order to attain such concentrations, a combination of rapid formation and relatively slow side-reaction loss of the aryne is needed.

Analogous [2 + 2] homodimerizations have been observed for the arynes generated from (6),1c (7),1c (8),7 (10),8 (13a) (but not polymer-bound 13b),10 (14),11a (15),11a and (23)15 (which decomposes thermally to form benzyne). Specific attempts to form [2 + 2] homodimers of arynes derived from (9),8 (16),11b (17)-(20),12b and (22)14 all failed; cycloheptyne does not react rapidly with itself, and no [2 + 2] homodimer is seen in reactions of (24) with LTA.16

Crossed aryne [2 + 2] reactions have been observed in LTA oxidations of mixtures of (1) + (8),7 (1) + (10),8 (1) + (14),11a (1) + (15),11a and, interestingly since no homodimer is formed from (16), (1) + (16)11b and (14) + (16)11b (shown in eq 5), but not (15) + (16).11b Angular benzannulation is thought to diminish the lifetime of arynes, making the last reaction especially unfavorable.11b

The Campbell-Rees procedure, as well as the anthranilic acid/alkyl nitrite method for generating benzyne, failed to give [2 + 2] product with 1,1-dichloro-2-methylpropene.17 The bis-aryne precursor (22) also failed to give [2 + 2] products with vinyl acetate, or 1,1-dimethoxyethylene.14 The latter alkene may be too rapidly oxidized by LTA. The homodimerization of benzyne is more rapid than [2 + 2] reactions of (E)- and (Z)-dichloroethene and vinyl acetate, under the original Campbell-Rees procedure.18 The modified procedure4 may lead to improvement.

[3 + 2] Cycloadditions.

The (1) + LTA method for generating benzyne is suitable for cycloadditions with mesionic compounds such as 3-phenylsydnone (26), which forms indazole (27) by extrusion of CO2 from the initially formed adduct (eq 6).19 Some related sulfur-containing mesionic species afford isolable adducts that undergo quite different extrusion processes under thermal or photochemical conditions.

Benzyne from (1) + LTA also reacts with CS2 to give the dithiacarbene intermediate (28) (eq 7).20 The further reactions of (28) depend on the reaction conditions.

[4 + 2] Cycloadditions.

Diels-Alder reactions are often (but not always, cf. thiophene21) more successful with the Campbell-Rees than with other benzyne-forming approaches. Further improvements are possible for many [4 + 2] reactions by use of the modified method mentioned earlier,4 and by carrying out the reactions at lower temperatures.4b The inverse temperature/yield relationship of Diels-Alder reactions of cycloheptyne nicely illustrates this point.16

A wide range of diene partners has been used for cycloaddition with benzyne derived from (1). Oxazoles, depending upon substituents and temperature, can give isolable cycloadducts (e.g. 29), which can in turn be converted to the analogous isobenzofuran (eq 8).4 Vinyl isocyanates afford lactams (eq 9).5,22 Isoquinolines are formed in the reaction with 1,2,4-triazines (eq 10).6 Compound (1) has also been used with metallocyclodienes such as substituted sila-23 and germacyclopentadienes,24 and digermacyclohexadienes.25 The adducts have been used to generate reactive intermediates such as dimethylsilylene (eq 11).23 Another notable example is the Diels-Alder reaction of azulene; interestingly, simultaneous addition of (1) and LTA was used in this study, but no comparison with the original Campbell-Rees conditions was noted. The cycloaddition takes place at the cyclopentadiene site as shown (eq 12).26

The very efficient reaction of benzyne with tetracyclone (2; see eq 1) has made it the diene of choice for demonstrating the formation of an aryne, and in some instances this reaction may be the only evidence for aryne formation; for example, 2,3-pyridyne from (17) was trapped by (2) in only 4% yield.12 Less efficient dienes include furan and anthracene; triptycene was isolated in only 12% yield by Campbell and Rees,18 but this reaction may have been partly limited by the solubility of anthracene. Limited solubility of the interesting bis-aryne precursor (22) also caused difficulties in some of its reactions.14

Other oxidizing agents were examined by Campbell and Rees, but none were found to be as good as Pb(OAc)4 for useful aryne applications.27 N-Bromosuccinimide apparently generates benzyne efficiently, but the reactive intermediate is largely trapped by rapid reaction with bromine. If a particular application requires the absence of acid, the (hazardous) benzyne precursor (23) can be used.

A possible alternative and related benzyne precursor, demonstrated only by reaction with (2), in 25% yield, is the nitrosobenzotriazole (30) (eq 13).28

1. (a) Campbell, C. D.; Rees, C. W. Proc. Chem. Soc. 1964, 296. (b) CC 1965, 192. (c) JCS(C) 1969, 742.
2. Foces-Foces, M. d. I. C.; Cano, F. H.; Claramunt, R. M.; Sanz, D.; Catalano, J.; Fabero, F.; Fruchier, A.; Elguero, J. JCS(P1) 1990, 237.
3. Houghton, P. G.; Rees, C. W. JCR(S) 1980, 303.
4. (a) Whitney, S. E.; Rickborn, B. JOC 1988, 53, 5595. (b) Whitney, S. E.; Winters, M.; Rickborn, B. JOC 1990, 55, 929.
5. Rigby, J. H.; Holsworth, D. D. TL 1991, 32, 5757.
6. Gonsalves, A. M. d'A.; Pinho e Melo, T. M. V. D.; Gilchrist, T. L. T 1992, 48, 6821.
7. Sato, M.; Ebine, S.; Tsunetsugu, J. JCS(P1) 1977, 1282.
8. Rees, C. W.; West, D. E. JCS(C) 1970, 583.
9. Cragg, G. M. L.; Giles, R. G. F.; Roos, G. H. P. JCS(P1) 1975, 1339.
10. Jayalekshmy, P.; Mazur, S. JACS 1976, 98, 6710.
11. (a) Barton, J. W.; Jones, S. A. JCS(C) 1967, 1276. (b) Barton, J. W.; Grinham, A. R. JCS(P1) 1972, 634.
12. (a) Fleet, G. W. J.; Fleming, I. JCS(C) 1969, 1758. (b) Fleet, G. W. J.; Fleming, I.; Philippides, D. JCS(C) 1971, 3948.
13. Christophe, D.; Promel, R.; Maeck, M. TL 1978, 4435.
14. Hart, H.; Ok, D. JOC 1986, 51, 979.
15. Keating, M.; Peek, M. E.; Rees, C. W.; Storr, R. C. JCS(P1) 1972, 1315.
16. Wittig, G.; Meske-Schueller, J. LA 1968, 711, 65.
17. O'Leary, M. A.; Stringer, M. B.; Wege, D. AJC 1978, 31, 2003.
18. Campbell, C. D.; Rees, C. W. JCS(C) 1969, 748.
19. (a) Nakazawa, S.; Kiyosawa, T.; Hirakawa, K.; Kato, H. CC 1974, 621. (b) Kato, H.; Nakazawa, S.; Kiyosawa, T.; Hirakawa, K. JCS(P1) 1976, 672.
20. Nakayama, J. JCS(P1) 1975, 525.
21. Reinecke, M. G.; Del Mazzo, D. JOC 1988, 53, 5799.
22. Rigby, J. H.; Holsworth, D. D.; James, K. JOC 1989, 54, 4019.
23. Sakurai, H.; Sakaba, H.; Nakadaira, Y. JACS 1982, 104, 6156.
24. (a) Ando, W.; Tsumuraya, T. TL 1986, 27, 3251. (b) Ando, W.; Itoh, H.; Tsumuraya, T. OM 1989, 8, 2759.
25. Sakurai, H.; Nakadaira, Y.; Tobita, H. CL 1982, 1855.
26. Cresp, T. M.; Wege, D. T 1986, 42, 6713.
27. Campbell, C. D.; Rees, C. W. JCS(C) 1969, 752.
28. Cadogan, J. I. G.; Thomson, J. B. CC 1969, 770.

Bruce Rickborn

University of California, Santa Barbara, CA, USA

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